Pharmaceutical Composition containing slightly water-soluble drug

ABSTRACT

The orally administrable pharmaceutical compositions containing a slightly water-soluble drug, characterized by improved stability and improved absorption of the drug from digestive tract into blood. The use of the compositions of the present invention enables decrease of the dose amount of a slightly water-soluble drug, which eventually leads to alleviation of pains and side effects on the part of patients.

This is a continuation of application Ser. No. 08/115,785 filed Sep. 3,1993 now U.S. Pat. No. 5,462,951 which is in turn a continuation of U.S.application Ser. No. 07/672,498 filed Mar. 20, 1991, abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to orally administrable pharmaceuticalcompositions containing a slightly water-soluble drug. Thepharmaceutical compositions for oral use according to the presentinvention are based on the characteristic properties of improvedabsorption From digestive tract into blood and improved stability.

Due to poor absorption of slightly water-soluble drugs, particularlydihydropyridine derivatives and lipoxygenase inhibitors, from digestivetract, there has been a strong demand for the development ofpharmaceutical formulations which afford good absorption in clinicalapplications. In order to improve absorption, addition of anabsorbefacient, improvement of dosage form designs, etc. are necessary,and generally employed means of formulation are pulverization ofcrystals, noncrystallization, addition of surfactants, cyelodextrininclusion, emulsification, dissolution in polyethylene glycol, vegetableoil, etc., or the like. However, none of these affords sufficientabsorption from digestive tract.

In addition, dihydropyridine derivatives are specifically unstable tolight, and for this reason, they are prepared into light-resistantpreparations or colored preparations and stored in light-resistantcontainers.

SUMMARY OF THE INVENTION

In an attempt to solve the aforementioned problems, an object of thepresent invention is to provide compositions containing a slightlywater-soluble drug which improve absorption by oral administration.Another object of the invention is to provide compositions wherein anunstable drug such as dihydropyridine derivatives is stabilized therein.

The present inventors have conducted intensive studies to provideeffective absorption of a slightly water-soluble drug from digestivetract and found that excellent bio-availability (BA) in oral use andstability of the drug can be achieved when the slightly water-solubledrug is formulated into a non-micelle composition by adding a fatty acidmonoglyceride and/or a polyoxyethylenesorbitan fatty acid ester to theslightly water-soluble drug, or formulated into a composition by furtheradsorbing same onto a porous inorganic substance, and that thethus-obtained composition serves well as a pharmaceutical compositionfor oral use.

The present invention has been completed on the basis of such findings,and the present invention relates to non-micelle pharmaceuticalcompositions for oral use wherein a slightly water-soluble drug isdissolved in a fatty acid monoglyceride and/or a polyoxyethylenesorbitanfatty acid ester, and to pharmaceutical compositions for oral usewherein the composition is further adsorbed onto a pharmaceuticallyacceptable porous inorganic substance.

DETAILED DESCRIPTION OF THE INVENTION

The slightly water-soluble drug in the invention is not particularlylimited as long as it has a solubility of 0.1 mg/ml or below in waterand is pharmacologically active. Specifically, the slightlywater-soluble drug means those which are slightly absorbed by oraladministration, have BA (%) of 10 or below, preferably 5 or below, morepreferably 3 or below, when orally administered after pulverization witha mortar [into 200 mesh (75 μm) or below] and suspending same in anaqueous solution of 0.5% sodium carboxymethyl-cellulose, and are easilydissolved in a fatty acid mono-glyceride and a polyoxyethylenesorbitanfatty acid ester. They are exemplified by dihydropyridine derivativesand lipoxygenase inhibitors such as caffeic acid derivatives, aromaticunsaturated ketone compounds and substituted stylene derivatives.

As the dihydropyridine derivatives, the following compounds arepreferably given. That is, dihydropyridine derivatives of the formula##STR1## wherein R¹, R² and R³ are the same or different and are analkyl, a cycloalkyl or an alkoxyalkyl, R⁴ and R⁵ are the same ordifferent and are hydrogen atom, a halogen, nitro, a halogenated alkyl,an alkylsulfonyl, a halogenated alkoxy, an alkylsulfinyl, an alkyl, acycloalkyl, an alkoxy, cyano, an alkoxycarbonyl or an alkylthio whereinR⁴ and R⁵ are not hydrogen atoms at the same time, X is a group ofvinylene or azomethine, A is an alkylene and B is --N(R⁶)₂ or ##STR2##where R⁶ and R⁷ are respectively hydrogen atom, an alkyl, a cycloalkyl,an aralkyl, an aryl or pyridyl, Ar is an aryl or pyridyl and n is aninteger of 0 to 2, or their acid addition salts (U.S. Pat. No.4,886,819, EP 257616).

The alkyl represented by R¹, R² or R³ is preferably a lower alkyl having1 to 6 carbon atoms, with further preference given to that having 1 to 4carbon atoms. The lower alkyl may have a lower cycloalkyl having 3 to 6carbon atoms on the alkyl terminal. As the cycloalkyl, a lowercycloalkyl having 3 to 6 carbon atoms is preferable. As the alkoxyalkyl,preferred are those having 3 to 7 carbon atoms.

The substituent represented by R⁴ or R⁵ is preferably at the 2- and/or3-position to the binding site with the dihydropyridine ring. As thehalogen at R⁴ or R⁵, particularly preferred are fluorine or chlorineatom, and as the alkyl and cycloalkyl, preferred are those mentioned asR¹ to R³. The alkoxy and the alkylthio preferably possess a lower alkylhaving 1 to 3 carbon atoms.

As the alkoxycarbonyl, there may be mentioned those having 2 to 4 carbonatoms. The halogen in halogenides is exemplified by those mentionedabove, and the halogenated alkyl and the halogenated alkoxy may be thatwhere some of the hydrogen atoms are halogenated or all of the hydrogenatoms are halogenated. The alkyl in alkylsulfonyl and alkylsulfinylincludes those exemplified as R¹ to R³.

As R⁴ and R⁵, preferred are cyano and halogenated alkyl (specifically,trifluoromethyl).

The alkyl and the cycloalkyl represented by R⁶ and R⁷ include thoseexemplified as R¹ to R³. Phenyl C₁₋₃ alkyl is preferred as the aralkyl,and phenyl and naphthyl are preferred as aryl. These aromatic rings mayhave tile same or different substituents at an optional position. Thesubstituents on the aromatic ring include those mentioned as R⁴ and R⁵.The pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl, which may havethe substituents mentioned above as R⁴ and R⁵.

The alkylene represented by A includes those having 2 to 4 carbon atoms,which may be a straight- or branched-chain.

The aryl and the pyridyl represented by Ar include those exemplified asR⁶ and R⁷ and may have the same substituents.

The ring represented by ##STR3## which is the 4-position substituent ofdihydropyridine, means a benzene ring when X is vinylene (--CH═CH--) andpyridine when X is azomethine (--CH═N--). An optional position of thering may bind to the 4-position of the dihydropyridine.

The substituents R⁴ and R⁵ are preferably at the ortho-and/ormeta-position to a carbon atom binding to the 4-position of thedihydropyridine.

As such compounds, the following can be mentioned.

2-(p-Dimethylaminophenyl)ethyl methyl2,6-dimethyl-4-(4-cyano-2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylateand its hydrochloride

2-(p-Dimethylaminophenyl)ethyl methyl 2,6-dimethyl-4-(2-trifluoromethyl-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate andits hydrochloride

2-(p-Dibenzylaminophenyl)ethyl methyl2,6-dimethyl-4-(4-cyano-2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylateand its hydrochloride

2-(p-Dibenzylaminophenyl)ethyl methyl2,6-dimethyl-4-(2-trifluoromethyl-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylateand its hydrochloride

2-[p-(4-Benzhydrylpiperadino)phenyl]ethyl methyl2,6-dimethyl-4-(4-cyano-2-pyridyl)-1,4-dihydropyridine-3,5dicarboxylateand its hydrochloride

2-[p-(4-Benzhydrylpiperadino)phenyl]ethyl methyl2,6-dimethyl-4-(2-trifluoromethyl-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylateand its fumarate

2-[p-(4-Benzhydrylpiperadino)phenyl]ethyl methyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5dicarboxylate andits hydrochloride

As tile lipoxygenase inhibitors, examples include compounds of thefollowing formulas 1 to 7.

1 Caffeic acid derivatives of the formula ##STR4## wherein R is an alkylhaving 3 to 10 carbon atoms which may be substituted by a halogen atom(U.S. Pat. No. 4,733,002, EP 163270).

The halogen atom as a substituent is preferably chlorine atom. The alkylsubstituted by the halogen includes, for example, --CO--O--(CH₂)₃ --CH₂--Cl, --CO--O--(CH₂)₃ --CHCl₂, ##STR5## As such compounds, there may bementioned caffeic acid propyl ester, caffeic acid butyl ester andcaffeic acid pentyl ester.

2 Caffeic acid derivatives of the formula ##STR6## wherein each of R⁸and R⁹ is hydrogen atom, an alkoxy having 1 to 4 carbon atoms orhydroxyl and X is a group of the formula --O--CH₂ --CH═CH--, --NH--CH₂--CH═CH--, --CH₂ --CH₂ --CH═CH--or --NH--(CH₂)_(n) --(n is 1 to 4) (U.S.Pat. No. 4,733,002, EP 163270).

When R⁸ and R⁹ are hydroxyls, they are preferably at the meta- andpara-positions. As such compounds, the following can be mentioned.

Caffeic acid-3,4-dihydrocinnamyl ester

Caffeic acid benzylamide

3 Caffeic acid derivatives of the formula ##STR7## wherein R¹⁰ and R¹¹are respectively hydroxyl or an alkoxy having 1 to 4 carbon atoms, and nis an integer of 6 to 14 (U.S. Pat. No. 4,733,002, EP 163270).

As such compounds, the following can be shown.

Caffeic acid hexylamide

Caffeic acid octylamide

Caffeic acid decylamide

3,4-Dimethoxycinnamic acid octylamide

4 Aromatic unsaturated ketone compounds of the formula ##STR8## whereinR' is hydroxyl, a phenyl which may be substituted by a lower alkoxy or ahalogen atom, specifically chlorine atom, or hydrogen atom, m is aninteger of 0 to 7 where it is an integer of 1 to 7 particularly 3 to 7when R' is hydrogen atom and 0 to 3 when R' is a phenyl which may besubstituted, n is 2 or 3 and X' is hydroxyl or a lower alkoxy adjacentto each other (U.S. Pat. No. 4,733,002, EP 163270).

As such compounds, the following can be shown.

1-(3',4'-Dihydroxyphenyl)-3-oxo-1-octene

1,5-bis(3',4'-Dihydroxyphenyl)-3-oxo-1-pentene

1-(3',4'-Bistetrahydropyranyloxyphenyl)-6-(3",4"-dimethoxy-phenyl)-3-oxo-1-hexene

5 Substituted stylene derivatives of the formula ##STR9## wherein R" ishydrogen atom or ##STR10## where R¹² and R¹³ are respectively hydrogenatom, hydroxyl, a lower alkoxy having 1 to 4 carbon atoms or a halogenatom, specifically chlorine atom, m is an integer of 1 to 8,particularly 3 to 7 when R" is hydrogen atom and an integer of 0 to 5,particularly 1 to 3 when R" is ##STR11## n is 2 or 3 and X" is hydroxylor a lower alkoxy having 1 to 4 carbon atoms which is adjacent to eachother (U.S. Pat. No. 4,733,002, EP 163270).

As such compounds, the following can be shown.

1-(3',4'-Dihydroxyphenyl)-1-hexene

1-(3',4'-Dihydroxyphenyl)-1-heptene

1-(3',4'-Dihydroxyphenyl)-1-oetene

1-(3',4'-Dihydroxyphenyl)-4-phenyl-1-butene

1-(3',4'-Dihydroxyphenyl)-4-(3",4"-dimethoxyphenyl)-1butene

6 Aromatic compounds of the formula ##STR12## wherein Y is--CH═CH--CONH--D, --C.tbd.C--E, --CH═CH--CO--O--C₁₋₃ alkylene ##STR13##--CH═CH--CO-alkyl, an alkyl having 3 or more carbon atoms which may besubstituted by hydroxyl or an alkoxycarbonyl, an alkylcarbonyl which maybe substituted by carboxyl or --CO--NH--J where D is an alkyl having 4to 8 carbon atoms, a phenyl which may be substituted by carboxyl or analkoxy having 1 to 4 carbon atoms, a heterocycle-alkyl (C₁₋₄) or anaralkyl (where the alkylene moiety of the aralkyl is substituted byhydroxyl), E is an alkyl having 4 to 8 carbon atoms or an alkyl(C₅₋₇)-carbonyl, G is hydroxyl, an alkyl having 2 to 7 carbon atomssubstituted by carboxyl or amino which may be substituted by a mono- ordi-alkyl(C₁₋₄) or phenyl substituted by carboxyl, J is ##STR14## whichmay be substituted by a halogen or carboxyphenyl and Z is a halogenatom; and R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are respectively hydrogen atom,hydroxyl, an aliphatic hydrocarbon residue having 3 or less carbon atomsand single or double bonds, (which may be substituted by hydroxyl), acarboxylalkyl or a lower alkoxy where R¹⁵ and R¹⁶ may form a naphthylcombinedly with the benzene ring X (the naphthyl is substituted by agroup selected from hydroxyl and alkoxy); with the proviso that when Yis --CH═CH--CO--alkyl, one of R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ is acarboxyalkyl, an aliphatic hydrocarbon residue having 3 or less carbonatoms and single or double bonds, (which may be substituted byhydroxyl), or two of R¹⁴, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ are hydroxyls which arenot adjacent to each other, and when Y is --CH═CH--alkyl, one of R¹⁴,R¹⁵, R¹⁶, R¹⁷ and R¹⁸ is an alky substituted by hydroxyl, or theirpharmacologically acceptable salts (U.S. Pat. No. 4,733,002, EP 163270).

The heterocycle of the heterocycle-alkyl represented by D preferablycontains 1 or 2 nitrogen, oxygen or sulfur atom as a hetero atom and isa 5- or 6-membered monocyclic heterocycle. The heterocycle may have asubstituent on the ring, and examples of the substituent includehydroxyl, oxo and halogen.

The alkyl moiety of the aralkyl group represented by D is preferablythose having 1 to 3 carbon atoms, with preference given to those wherethe carbon atom which binds to the aryl group is substituted by onehydroxyl.

The aryl moiety of the aralkyl in ##STR15## represented by J which maybe substituted by a halogen, is preferably phenyl or a phenylsubstituted by hydroxyl, halogen, etc., and the alkyl moiety ispreferably those having 1 to 3 carbon atoms. The alkyl moiety may besubstituted by phenyl. The alkylene moiety includes those having 2 to 3carbon atoms.

The alkyl moiety in --CH═CH-alkyl represented by Y includes those having4 to 6 carbon atoms.

The alkyl moiety in --CH═CH--CO-alkyl represented by Y includes thosehaving 4 to 6 carbon atoms.

The alkoxycarbonyl in the alkyl having 3 or more carbon atomsrepresented by Y, which may be substituted by hydroxyl or alkoxycarbonylis preferably those having 2 to 5 carbon atoms, and the alkyl having 3or more carbon atoms includes those having 3 to 8 carbon atoms, and acarbon atom adjacent to the X ring is preferably substituted byhydroxyl, and the alkoxycarbonyl is preferably the terminal carbon atomof the alkyl having 3 or more carbon atoms. The alkyl having 3 or morecarbon atoms is preferably a straight chain.

As regards the alkylcarbonyl represented by Y, which may be substitutedby carboxyl, the alkyl moiety of the alkylcarbonyl is preferably thosehaving 1 to 4 carbon atoms and a straight chain.

The aliphatic hydrocarbon residue having 3 or less carbon atomsrepresented by R¹⁴ to R¹⁸, which comprises single bonds or double bondsand may be substituted by hydroxyl includes alkyl, alkenyl andhydroxyl-substituted alkyl. The alkyl moiety of the carboxyalkylrepresented by R¹⁴ to R¹⁸ is preferably those having 3 or less carbonatoms, and examples of the carboxyalkyl include carboxymethyl,carboxyethyl and carboxypropyl. The alkoxy represented by R¹⁴ to R¹⁸ ispreferably those having 1 to 5 carbon atoms.

When R¹⁵ and R¹⁶ combinedly form a naphthyl with the benzene ring, thealkoxy to be substituted preferably has carbon atoms of 3 or below. Thesubstituent on the naphthyl may be at any optional position of thenaphthalene skeleton, with preference given to the 2- and/or 3-position.

As such compounds, the following can be shown.

Caffeic acid p-n-butylanilide

Caffeic acid m-n-octylanilide

Caffeic acid 3,4-dimethoxyanilide

Caffeic acid 2-(2-pyridyl)ethylamide

Caffeic acid 3-morpholinopropylamide

Caffeic acid 3-(2-oxo-3-pyrrolidinyl)propylamide

Caffeic acid norephedrinamide

3,4-Dimethoxy cinnamic acid norephedrinamide

3,4-Dimethoxy perphenazine cinnamate

1-(3,4-Dihydroxyphenyl)octan-1-ol

1-(3,4-Dihydroxyphenyl)hexan-1-ol

1-(3,4-Dihydroxyphenyl)butan-1-ol

4-Octylcatechol

4-Hexylcatechol

4-Butylcatechol

1-(3,4-Dimethoxyphenyl)-1-octyne

1-(3,4-Dihydroxyphenyl)-1-octyne

1-(3,4-Dihydroxyphenyl)-1-hexyne

1-(3,4-Dihydroxyphenyl)-1-butyne

1-(3,4-Dimethoxyphenyl)-1-decyn-3-one

1-(3,4-Dihydroxyphenyl)-1-octyn-3-one

1-(3,4-Dihydroxyphenyl)-8-hydroxy-3-oxo-1-octene

1-(3,4-Dihydcoxyphenyl)-6-oxo-7-octene acid

1-(3,4-Dihydroxyphenyl)-8-dimethylamino-1-octen-3-one

1-(3,4-Dihydroxy-2-propylphenyl)-3-oxo-1-octene

1-[5-(2-Propenyl)-3,4-dihydroxyphenyl ]1-octen-3-one

Ethyl 2,3-dimethoxynaphthalene-7-carboxylic acid4-[α-(p-chlorophenyl)benzyl]-1-piperadinylamide

Ethyl 2,3-dihydroxynaphthalene-7-carboxylic acid2-[4{α-(p-chlorophenyl)}benzyl]piperadinylamide

2,3-Dihydroxynaphthalene-7-carboxylic acid o-carboxyphenylamide

4-(2,3-Dihydroxynaphthalen-7-yl)-4-oxobutyric acid

2,3-Dihydroxy-7-(1-oxobutyl)naphthalene

2,3-Dihydroxy-7-butylnaphthalene

Ethyl 4-(2,3-dihydroxynaphthalen-7-yl)-butyrate

1-[2-(2-Carboxyethyl)-3,4-dihydroxyphenyl]-3-oxo-1-octene

1-(2,4-Dihydroxyphenyl)-1-octen-3-one

1-(2,5-Dihydroxyphenyl)-1-octen-3-one

1-(3,5-Dihydroxyphenyl)-1-octen-3-one

3,4-Dihydroxy-2'-carboxychalcone

3,4-Dihydroxy-4'-carboxychalcone

1-(2-Hydroxy-3-hydroxymethylphenyl)-1-octen-3-one

1-(3-Hydroxy-2-hydroxymethylphenyl)-1-octen-3-one

1-(3-Hydroxy-4-hydroxymethylphenyl)-1-octen-3-one

1-(4-Hydroxy-3-hydroxymethylphenyl)-1-octen-3-one

1-(4-Hydroxy-3-hydroxymethylphenyl)-1-hexene

N-(4'-Hydroxy-3'-hydroxymethylcinnamoyl)anthranilic acid

7 Bis-S-alkylbenzene derivatives of the formula ##STR16## wherein eachof R¹⁹ and R.sup.° is an alkyl having 1 to 4 carbon atoms, R²¹ ishydrogen atom, an alkyl having 1 to 4 carbon atoms, an acyl having 1 to5 carbon atoms, an alkoxyalkyl, an alkylcarbamoyl or a phosphate residueand R²² is a group of the formula --C_(m) H_(2m) --R²³ where R²³ ishydrogen atom or a cycloalkyl having 5 to 7 carbon atoms which may besubstituted by hydroxyl and m is an integer of 3 to 15, a substituent ofthe formula --C_(n) H_(2n) --R²⁴ where R²⁴ is hydrogen atom, an acylhaving 1 to 5 carbon atoms or an alkyl having 1 to 4 carbon atoms whichmay be substituted by hydroxyl and n is an integer of 3 to 15, or abenzhydrylpiperazylalkyl (U.S. Pat. No. 4,933,329, EP 319947).

The alkyl and the alkoxy are not particularly limited as long as theyhave 1 to 4 carbon atoms.

The alkoxy and alkyl moieties in the alkoxyalkyl have 1 to 4 carbonatoms each, and include, for example, methoxymethyl.

The alkyl moiety in the alkylcarbamoyl has 1 to 4 carbon atoms andexamples thereof include methylcarbamoyl, ethylcarbamoyl andpropylcarbamoyl.

The alkyl moiety in the benzhydrylpiperazylalkyl has 1 to 4 carbon atomsand examples thereof include benzhydrylpiperazylmethyl, and so on.

It is preferable that the substituents R¹⁹ --S and R²⁰ --S on the phenylring be at the meta-position to each other.

In particular, the substituent R²¹ --O in the following formula ispreferably at the ortho-position to each of the other two substituentsmentioned above. Namely, compounds of the following formula areparticularly preferable. ##STR17## wherein R¹⁹, R²⁰, R²¹ and R²² are asdefined above.

Particularly preferred positions are R²¹ --O at the 1-, R¹⁹ --S at the2, R²² at the 4and S--R²⁰ at the 6-positions. Namely, compounds of thefollowing formula are particularly preferable. ##STR18##

wherein R¹⁹, R²⁰, R¹² and R²² are as defined above.

As such compounds, the following can be shown.

8-{3,5-bis(Methylthio)-4-hydroxyphenyl} octanol

2,6-bis(Methylthio)-4-octylphenol

2,6-bis(Methylthio)-4-octylannisole

2,6-bis(Methylthio)-4-octylphenyl-N-isopropylcarbamate

2,6-bis(Methylthio)-4-octylphenyl-N-methylcarbamate

2,6-bis(Methylthio)-4-octylphenyl-acetate

2,6-bis(Methylthio)-4-octylphenyl-phosphate

4-[5-(4-Methoxymethoxyphenyl)pentyl]-cyclohexanol

cis-4-[5-(3,5-bis(Methylthio)-4-hydroxyphenyl)pentyl]cyclohexanol

trans-4-[5-(3,5-bis(Methylthio)-4-hydroxyphenyl)pentyl]cyclohexanol

2,6-bis(Methylthio)-4-(8-methoxyoctyl)phenol

2,6-bis(Methylthio)-4-{8-(2-hydroxyethoxy)octyl}phenol

3,5-bis(Methylthio)-4-methoxymethoxybenzaldehyde propyleneacetal

1-{3,5-bis(sec-Butylthio)-4-hydroxyphenylmethyl}-4-(1,1diphenylmethyl)piperazine

The fatty acid monoglyceride is a monoester of fatty acid and glycerinwhere the fatty acid preferably has 14 to 28 carbon atoms, morepreferably 16 to 18 carbon atoms and the number of unsaturated bonds,particularly double bonds, when the fatty acid is unsaturated is 1 or 2.Specific examples of unsaturated fatty acid include palmitoleic acid,oleic acid, linoleic acid, linolenic acid, or the like, and examples ofsaturated fatty acid include myristic acid, palmitic acid, stearic acid,behenic acid, hepta-cosanoic acid, or the like. As the fatty acid, thosehaving the above carbon atoms may be used solely or in mixture, withpreference given to unsaturated fatty acids.

In the present invention, the fatty acid moiety of thepolyoxyethylenesorbitan fatty acid ester preferably has 10 to 18 carbonatoms, which is exemplified by polyoxyethylenesorbitan fatty acid esterssuch as polyoxyethylenesorbitan monooleate, polyoxyethylenesorbitanmonostearate, polyoxyethylenesorbitan monopalmitate,polyoxyethylenesorbitan monolaurate, or the like.

Further, a nonionic surfactant other than the above-mentionedpolyoxyethylenesorbitan fatty acid esters may be co-used, and examplesof such surfactants include polyoxyethylenesorbit fatty acid ester,polyoxyethylene hydrogenated castor oil, polyglycerin fatty acid ester,or the like. The nonionic surfactant to be used in the present inventionis not particularly limited and those acceptable as pharmaceuticaladditives may be used. The HLB value (hydrophile-lipophile balance) ispreferably not less than 3, preferably 10 to 20.

The solubility of the slightly water-soluble drug in a fatty acidmonoglyceride and a nonionic surfactant is about 10-500 mg/ml.

No limitation is posed on the porous inorganic substance of the presentinvention as long as the substance efficiently adsorbs the non-micellecompositions obtained by adding a fatty acid monoglyceride and/or apolyoxyethylenesorbitan fatty acid ester and is pharmacologicallyacceptable, and examples include magnesium aluminate silicate, silicondioxides such as light silicic acid anhydride and silicon dioxidehydrate, or the like.

The proportion of each ingredient in the non-micelle pharmaceuticalcompositions for oral administration is not particularly limited butadjusted suitably depending on the kind of tile slightly water-solubledrug.

For example, when either the fatty acid monoglyceride or thepolyoxyethylenesorbitan fatty acid ester is used solely, it ispreferably used in an amount of 1 to 100 parts by weight, preferably 5to 60 parts by weight per 1 part by weight of the slightly water-solubledrug. When the fatty acid monoglyceride and the polyoxyethylenesorbitanfatty acid ester are used combinedly, they are preferably used in anamount of 1 to 100 parts by weight, preferably 10 to 50 parts by weightper 1 part by weight of the slightly water-soluble drug.

Further, when a nonionic surfactant other than thepolyoxyethylenesorbitan fatty acid ester is also used, a fatty acidmonoglyceride and/or a polyoxyethylenesorbitan fatty acid ester and anonionic surfactant are used in an amount of 1 to 100 parts by weight,preferably 10 to 50 parts by weight per 1 part by weight of the slightlywater-soluble drug.

In the pharmaceutical composition for oral use prepared by adsorptiononto the porous inorganic substance, the porous inorganic substance isused in an amount of 1 to 100 parts by weight, preferably 2 to 10 partsby weight per 10 parts by weight of the aforementioned non-micellepharmaceutical composition for oral use.

The non-micelle pharmaceutical compositions of the present invention arenormally prepared by dissolving a slightly water-soluble drug in a fattyacid monoglyceride and/or a polyoxyethylenesorbitan fatty acid ester,and a nonionic surfactant other than the polyoxyethylenesorbitan fattyacid ester. Other additives such as stabilizers, antiseptics, extenders,etc. may be further added to the composition. The composition isnormally formulated into capsule preparations, specifically into softcapsules.

The pharmaceutical compositions prepared by adsorption onto a porousinorganic substance are normally prepared in the form of powders andgranules and the adsorption is conducted by a method known per se. Thatis, the pharmaceutical composition comprising adsorption onto a porousinorganic substance is prepared by mixing a non-micelle pharmaceuticalcomposition for oral use of the present invention with a porousinorganic substance. The powders thus obtained may be formulated intopowder preparations by adding an excipient for formulation such asmannitol, etc., packed in capsules or tableted by a conventional method.

EXAMPLE 1

2-[p-(4-Benzhydrylpiperadinophenyl)ethyl methyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate]hydrochloride (20.1 g) is added to unsaturated fatty acid monoglyceride(Kao, "Excel O-95R", 650 g), followed by dissolution and stirring at 40°C. to give a non-micelle solution.

EXAMPLE 2

2-[p-(4-Benzhydrylpiperadinophenyl)ethyl methyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate]hydrochloride (20.1 g) is added to polyoxyethylenesorbitan monooleate(Nikko Chemical, "TO-10M", 650 g), followed by dissolution and stirringat 40° C. to give a non-micelle solution.

EXAMPLE 3

2-[p-(4-Benzhydrylpiperadinophenyl)ethyl methyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate]hydrochloride (20.1 g) is added to a mixture of unsaturated fatty acidmonoglyceride (Kao, "Excel O-95R") and polyoxyethylenesorbitanmonooleate (Nikko Chemical, "TO-10M") in a proportion of 1:1 (650 g),followed by dissolution and stirring at 40° C. to give a non-micellesolution.

EXAMPLE 4

2-[p-(4-Benzhydrylpiperadinophenyl)ethyl methyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate]hydrochloride (20.1 g) is added to a mixture of unsaturated fatty acidmonoglyceride (Kao, "Excel O-95R") and polyethylene glycol (PEG 400) ina proportion of 1:1 (650 g), followed by dissolution and stirring at 40°C. to give a non-micelle solution.

COMPARISON EXAMPLE 1

2-[p-(4-Benzhydrylpiperadinophenyl)ethyl methyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate]hydrochloride (20.1 g) is added to polyethylene glycol (PEG 400, 650 g),followed by dissolution and stirring at 40° C. to give a non-micellesolution.

COMPARISON EXAMPLE 2

2-[p-(4-Benzhydrylpiperadinophenyl)ethyl methyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboylate]hydrochloride (10 g) is pulverized with a mortar and mixed with lactose(190 g) to give 200 g of a powder for capsules.

EXAMPLE 5

2-[p-(4-Benzhydrylpiperadinophenyl)ethyl methyl2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine-3,5-dicarboxylate]hydrochloride (20.1 g) is added to unsaturated fatty acid monoglyceride(Kao, "Excel O-95R", 650 g), followed by dissolution and stirring at 40°C. to give a non-micelle solution. The thus-obtained solution (600 g)and magnesium alminate metasilicate (Fuji Kagaku Sangyo, "Neusilin US₂", 370 g) are mixed with a stirring-granulator. Thereto is addedCarmellose sodium A type (30 g) for mixing and stirring, followed byaddition of purified water (250 ml) to give granules. The granules aredried at 40° C. for 17 hours with a forced-air drier and passed througha sieve of 42-200 mesh to give 550 g of fine granules for capsules.

EXAMPLE 6

2-[p-(4-Benzhydrylpiperadinophenyl)ethyl methyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine -3,5-dicarboxylate]hydrochloride (20.1 g) is added to polyoxyethylcnesorbitan monooleate(Nikko Chemical, "TO10M", 650 g), followed by dissolution and stirringat 40° C. to give a non-micelle solution. The thus-obtained solution(600 g) and magnesium alminate metasilicate (Fuji Kagaku Sangyo,"Neusilin US₂ ", 370 g) are mixed with a stirring-granulator. Thereto isadded Carmellose sodium A type (30 g) for mixing and stirring, followedby addition of purified water (250 ml) to give granules. The granulesare dried at 40° C. for 17 hours with a forced-air drier and passedthrough a sieve of 42-200 mesh to give 550 g of fine granules forcapsules.

EXAMPLE 7

2-[p-(4-Benzhydrylpiperadinophenyl)ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate]hydrochloride (20.1 g) is added to a mixture of unsaturated fatty acidmonoglyceride (Kao, "Excel O-95R") and polyoxyethylenesorbitanmonooleate (Nikko Chemical, "TO-10M") in a proportion of 1:1 (650 g),followed by dissolution and stirring at 40° C. to give a non-micellesolution. The thus-obtained solution (600 g) and magnesium alminatemetasilicate (Fuji Kagaku Sangyo, "Neusilin US₂ ", 370 g) are mixed witha stirring-granulator. Thereto is added Carmellose sodium A type (30 g)for mixing and stirring, followed by addition of purified water (250 ml)to give granules. The granules are dried at 40° C. for 17 hours with aforced-air drier and passed through a sieve of 42-200 mesh to give 550 gof fine granules for capsules.

EXPERIMENT EXAMPLE 1 Absorption by Oral Administration

The absorption and stability of the pharmaceutical compositions asobtained in Examples 1 to 7 and Comparison Examples 1 and 2 aresummarized in Table 1.

The absorption evaluation was conducted as follows. That is, acomposition of the present invention was administered to a beagleweighing about 10 kg after fasted for 20 hours before the administrationin a dose of 3 mg/0.1 ml/kg, and sample blood was taken from radialiscutaneous vein at given time intervals up to 24 hours after theadministrations. The plasma of the blood sample was centrifuged,deproteinized with acetonitrile and determined by high performanceliquid chromatography (HPLC) using a reversed-phase column [ODS (C₁₈), 4μ, 3.9 φ×150 mm, Japan Waters]. The BA% was estimated on the basis ofthe blood concentration.

                  TABLE 1                                                         ______________________________________                                                                  Absorption                                                  Additives used    (BA %)                                              ______________________________________                                        Ex. 1     Excel O-95R         26.0                                            Ex. 2     TO-10M              24.3                                            Ex. 3     Excel O-95R + TO-10M (1:1)                                                                        25.6                                            Ex. 4     PEG 400 + Excel O-95R (1:1)                                                                       21.7                                            Ex. 5     Excel O-95R/Neusilin                                                                              23.0                                            Ex. 7     Excel O-95R + TO-10M (1:1)/                                                                       29.4                                                      Neusilin                                                            Comp. Ex. 1                                                                             PEG 400             1.2                                             Comp. Ex. 2                                                                             no additive         0.3                                             ______________________________________                                    

EXPERIMENT EXAMPLE 2 Stability of the Pharmaceutical Composition of theInvention

Using the pharmaceutical compositions as prepared in Examples 5 to 7,tile stability was examined by a storage test at 40° C. The content ofanalogous substance and appearance 4 weeks later are summarized in Table2.

                  TABLE 2                                                         ______________________________________                                                      Stability (60° C., 4 weeks)                                              content of analo-                                             Additives used  gous substance (%)*                                                                         appearance                                      ______________________________________                                        Excel O-95R/    2.9           colored                                         Neusilin (Ex. 5)                                                              TO-10M/Neusilin 1.2           no change                                       (Ex. 6)                                                                       Excel O-95R + TO-10M                                                                          1.6           no change                                       (1:1)/Neusilin (Ex. 7)                                                        ______________________________________                                         *: dihydropyridine decomposing substance                                 

The pharmaceutical compositions for oral administration of the presentinvention markedly improve absorption of slightly water-soluble drugssuch as dihydropyridine, etc. as evidenced in Experiment Example 1 andthe stability of the slightly water-soluble drugs in a powdery form isexcellent as evidenced in Experiment Example 2.

The use of the pharmaceutical compositions for oral administration ofthe present invention enables decreasing of the dose amount of slightlywater-soluble drugs, which eventually leads to alleviation of pains andside effects on the part of patients.

What is claimed is:
 1. A non-micelle pharmaceutical composition for oraladministration comprising a dihydropyridine derivative of the formula##STR19## wherein R¹, R², and R³ are the same or different and are analkyl, a cycloalkyl or an alkoxyalkyl, R⁴ and R⁵ are the same ordifferent and are hydrogen atom, a halogen, nitro, a halogenated alkyl,an alkylsulfonyl, a halogenated alkoxy, an alkylsulfinyl, an alkyl, acycloalkyl, an alkoxy, cyano, an alkoxycarbonyl or an alkylthio whereinR⁴ and R⁵ are not hydrogen atoms at the same time, X is a group ofvinylene or azomethine, A is an alkylene and B is --N(R⁶)₂ or ##STR20##wherein R⁶ and R⁷ are respectively hydrogen atom, an alkyl, acycloalkyl, an aralkyl, an aryl or pyridyl, Ar is an aryl or pyridyl andn is an integer of 0 to 2, or their acid addition salts dissolved in apolyoxyethylenesorbitan fatty acid ester and a fatty acid monoglyceride.2. A pharmaceutical composition for oral administration as claimed inclaim 1, wherein the dihydropyridine derivative is selected from thegroup consisting of2-(p-Dimethylaminophenyl)ethyl methyl2,6-dimethyl-4-(4-cyano-2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylate and its hydrochloride, 2-(p-Dimethylaminophenyl)ethylmethyl2,6-dimethyl-4-(2-triflouromethyl-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylateand its hydrochloride, 2-(p-Dibenzylaminophenyl)ethyl methyl2,6-dimethyl-4-(4-cyano-2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylateand its hydrochloride, 2-(p-Dibenzylaminophenyl)ethyl methyl2,6-dimethyl-4-(2-trifluoromethyl-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylateand its hydrochloride, 2-[p-(4-Benzhydrylpiperadino)phenyl]ethyl methyl2,6-dimethyl-4(4-cyano-2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylateand its hydrochloride, 2-[p-(4-Benzhydrylpiperadino)phenyl]ethyl methyl2,6-dimethyl-4-(2-trifluoromethyl-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylateand its fumarate, and 2-[p-(4-Benzhydrylpiperadino)phenyl]ethyl methyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate andits hydrochloride.
 3. A pharmaceutical composition for oraladministration as claimed in claim 1, wherein the fatty acidmonoglyceride is of a fatty acid having 14 to 28 carbon atoms.
 4. Apharmaceutical composition for oral administration as claimed in claim 3wherein the fatty acid having 14 to 28 carbon atoms is selected from thegroup consisting of palmitoleic acid, oleic acid, linoleic acid andlinolenic acid.
 5. A pharmaceutical composition for oral administrationas claimed in claim 1, wherein the polyoxyethylenesorbitan fatty acidester is of a fatty acid having 10 to 18 carbon atoms.
 6. Apharmaceutical composition for oral administration as claimed in claim5, wherein the polyoxyethylenesorbitan fatty acid ester is selected fromthe group consisting of polyoxyethylenesorbitan monooleate,polyoxyethylenesorbitan monostearate, polyoxyethylenesorbitanmonopalmitate and polyoxyethylenesorbitan monolaurate.
 7. Apharmaceutical composition for oral administration as claimed in claim1, wherein the fatty acid monoglyceride and the polyoxyethylenesorbitanfatty acid ester are present in an amount of 1 to 100 parts by weightper 1 part by weight of drug.
 8. A pharmaceutical composition for oraladministration as claimed in claim 1, which further comprises a nonionicsurfactant of HLB (hydrophile-lipophile balance) not less than 3 otherthan a polyoxyethylenesorbitan fatty acid ester.
 9. A pharmaceuticalcomposition for oral administration as claimed in claim 8, wherein thenonionic surfactant is selected from the group consisting ofpolyoxyethylene hydrogenated castor oil and polyglycerin fatty acidester.
 10. A pharmaceutical composition for oral administration asclaimed in claim 8, wherein the fatty acid monoglyceride, thepolyoxyethylenesorbitan fatty acid ester and the nonionic surfactantother than polyoxyethylenesorbitan fatty acid ester are present in anamount of 1 to 100 parts by weight per 1 part by weight of a slightlywater-soluble drug.
 11. A pharmaceutical composition for oraladministration as claimed in claim 1, wherein the dihydropyridinederivative is 2-[p-(4-benzhydrylpiperazino)phenyl]ethyl methyl2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylatehydrochloride.